Detoxification of certain highly lipophilic endogenous substrates and noxious foreign compounds, such as environmental pollutants, requires a multistep process involving phase I and phase II enzyme systems. Previously, with inbred strains of mice, research in this Branch has established that certain monooxygenases (phase I enzymes) are regulated at a few genetic loci and that expression of enzyme induction is dominant or codominant in response to aromatic hydrocarbon treatment. Recently, studies were initiated to understand the impact of secondary reactions on the detoxification process, since the products of the monooxygenase system can serve as substrate for conjugation via the UDP glucuronyl transferase system (phase II enzymes). In hepatic tissue from aromatic hydrocarbon treated mice, it has been shown that induction of a transferase enzyme system lags behind the time course of induction of a certain monooxygenase system, is genetically linked to the induction of the monooxygenase, and is expressed as a codominant trait in progeny from backcrosses and intercrosses of the prototype strains of mice. Since many noxious foreign compounds are metabolized initially via the monooxygenase system and subsequently by the transferase system or one of several other drug-metabolizing enzymes, an understanding of the functional relationship of these various enzymes might explain why carcinogenesis, toxicity, teratogenesis, and/or mutagenesis are caused by certain xenobiotics and not by others.